Process for the preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride

ABSTRACT

The invention relates to a process for the preparation of anagrelide, and for the preparation of intermediates for use in preparing anagrelide. The invention also relates to the intermediates per se, in particular compounds of Formula (V): 
                         
where R constitutes a suitable leaving group, which may not be hydrogen. The R group may be selected from: (i) —SiR 1   3 , (ii) —CH 2 Ar, (iii) —COOR 2 , and (iv) sulfonates such as —SO 2 R 3 .

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a filing under 35 U.S.C. 371 of InternationalApplication No. PCT/GB2008/000430 filed Feb. 6, 2008, entitled “Processfor the Preparation of Ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycinehydrochloride,” claiming priority of Indian Patent Application No.215/MUM/2007 filed Feb. 6, 2007, which applications are incorporated byreference herein in their entirety.

FIELD OF INVENTION

The present invention relates to an improved process for the preparationof ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride which is akey intermediate used in the preparation of anagrelide,(6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2 (3H)-one.

BACKGROUND OF THE INVENTION

Anagrelide, is a potent reducer of platelet count induced by a varietyof aggregating agents and has the following structure

U.S. Pat. No. 4,146,718 discloses the process for the preparation ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride from1,2,3-trichlorobenzene as depicted in Scheme I via2,3-dichloro-6-nitrobenzonitrile, which involves the use of poisonousreagents, such as cuprous cyanide. Cyanation is carried out at atemperature of 165° C. which is highly exothermic, uncontrollable andnot scalable. 2,3-dichloro-6-nitrobenzonitrile has extreme toxic andskin-irritant properties. Diborane is a flammable gas, used for thereduction of 2,3-dichloro-6-nitrobenzonitrile. The reduction reaction isexothermic, uncontrollable and not feasible industrially.

U.S. Pat. No. 5,801,245 discloses process for the preparation ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride from2,3-dichloro toluene as depicted in Scheme II.

The reaction involves a radical halogenation of the toluene group. Thematerial is purified by column chromatography at each stage which makesthe process more tedious and it is not viable industrially. The use of achromatographic solvent, such as chloroform (which is a knowncarcinogen), is disadvantageous with respect to industrial application.

US 2003/0060630 discloses a method for makingethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride from2,3-dichloro benzaldehyde as depicted in Scheme III.

In step (b), the reduction reaction is carried out in high boilingsolvents like toluene. The reduction in step (b) and the chlorination instep (c) are sluggish. Also, the chlorination reaction is exothermic anduncontrollable, which leads to formation of more impurities and therebyresulting in low yield (page 4, column 2, and page 5, column 1: 65%).Hence, this prior art process is not viable for industrial scale up.

Because of the difficulties encountered in the processes disclosed inthe prior art, there is a need to develop more efficient and economicalsynthetic route for the preparation ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, which issuitable for industrial scale up. The present invention relates to a newprocess for the synthesis of Ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycinehydrochloride.

An object of the present invention is to provide a novel process for thesynthesis of the intermediate ethylN-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride.

Another object of the present invention is to provide novel process forsynthesis of anagrelide.

Yet, another object of the present invention is to provide a simplenovel process which is useful for application on an industrial scale.

SUMMARY OF THE INVENTION

The present invention provides a new process for the synthesis ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, a compound ofFormula (I)

which comprises the following steps;

-   (i) reducing 2,3-dichloro-6-nitro benzaldehyde Formula (III),

to form 2,3-dichloro-6-nitro benzyl alcohol of Formula (IV),

-   (ii) reacting 2,3-dichloro-6-nitro benzyl alcohol with suitable    compound to obtain compound of Formula (V),

where R constitutes a suitable leaving group, which may not be hydrogen.

Preferably, the group R is selected from:

i) —SiR¹ ₃, where R¹ is a substituted or unsubstituted alkyl. R¹ ispreferably C₁ to C₆, more preferably C₁ to C₄ straight or branched chainalkyl group. Most preferably R¹ is methyl.

ii) —CH₂Ar, where Ar stands for aryl, preferably a substituted orunsubstituted phenyl group.

iii) —COOR², where R² is alkyl or aryl. When R² is alkyl it ispreferably C₁ to C₆, more preferably C₁ to C₄ straight or branched chainalkyl. When R² is alkyl, it is most preferably methyl. The aryl group ispreferably a substituted or unsubstituted phenyl group.

iv) sulfonates such as —SO₂R³, where R³ is alkyl or aryl. When R³ isalkyl it is preferably C₁ to C₆, more preferably C₁ to C₄ straight orbranched chain alkyl. When R³ is alkyl, it is most preferably methyl.The aryl group is preferably a substituted or unsubstituted phenylgroup.

The most preferred —O—R groups in Formula (V) are mesylate, besylate andtosylate.

(iii) Alkylating the compound of Formula (V) with glycine ethyl ester ina suitable solvent, using a base, and then converting to a salt,preferably the hydrochloride salt, in a suitable solvent, to obtaincompound of Formula (I).

It will be appreciated that step (i) is optional, in that the compoundof Formula (IV) may be provided by any suitable means.

Thus, according to one aspect of the invention there is provided aprocess for the synthesis of a compound of Formula (V)

where R is a suitable leaving group, which may not be hydrogen, saidprocess comprising reacting a compound of Formula (IV)

with suitable compound to obtain the compound of Formula (V).

Preferably, the reaction is carried out in the presence of an alkyl oraryl sulphonyl halide, especially a methyl sulphonyl halide, such asmethyl sulphonyl chloride. Preferably also, the reaction is carried outin the presence of a base, such as triethylamine. Preferably, thereaction is carried out at a temperature of 35° C., or less.

According to another aspect of the invention there is provided a processfor preparing a compound of Formula (I′),

said processing comprising alkylating a compound of Formula (V)

where R constitutes a suitable leaving group, which may not be hydrogen(preferably as described above) with glycine ethyl ester in a suitablesolvent, using a base.

The compound of Formula (I′) may be converted to a salt in the presenceof a suitable solvent. Most preferably, the compound of Formula (I′) isconverted to the hydrochloride salt in a suitable solvent, to obtaincompound of Formula (I).

The reaction temperature of the alkylation step is preferably 60° C., orlower, more preferably 40° C., or lower.

According to another aspect of the invention there is provided acompound of Formula (V):

where R is a suitable leaving group, which may not be hydrogen, and ispreferably as described above.

In another aspect, the present invention provides a process to prepareanagrelide of Formula (II) which comprises the following steps:

-   (i) Forming a salt of the compound of Formula (I′) (the    hydrochloride salt is preferred, Formula (I) using the process    described above;-   (ii) reducing the nitro group of Formula (I) with a suitable    reducing agent to convert it to an amine of Formula (VI),

-   (iii) reacting the compound of Formula (VI) with a cyanogen halide    to form compound of Formula (VII),

wherein halide is chloro, bromo or iodo;

-   (iv) cyclising compound of Formula (VII), to form compound of    Formula (II), i.e. anagrelide.

The anagrelide formed by the processes described above may be combinedwith a suitable carrier to make a pharmaceutical composition. Suchcompositions may be used to reduce platelet count induced by a varietyof aggregating agents.

DETAILED DESCRIPTION OF THE INVENTION

The process according to the invention will now be described in moredetail below.

The process for the preparation ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride according tothe invention is depicted in the reaction scheme below. Bracketsindicate intermediates that could be isolated but are not usuallyisolated in the integrated process.

wherein R represents a suitable leaving group, wherein R is not hydrogenand preferably has the meaning described above in relation to Formula(V).

(i) 2,3-dichloro-6-nitrobenzaldehyde, of Formula (III) is reduced togive the corresponding alcohol of Formula IV. The reducing agent ispreferably selected from sodium borohydride, potassium borohydride,sodium cyanoborohydride and tetramethyl ammonium borohydride. Thereaction is preferably carried out in a solvent, which is preferably aC₁ to C₆ straight chain or branched chain alcohol, especially methanol,ethanol, isopropanol or n-butanol; or a chlorinated solvent such aschloroform, methylene chloride, carbon tetrachloride, ethylene chloride,with methylene chloride being preferred. The reaction is preferablycarried out at a temperature ranging from 0° C. to the refluxtemperature of the solvent, and the reaction time may vary from 1 to 3hrs.

(ii) According to a particular feature of the present invention, thehydroxymethyl functionality of phenyl methyl alcohol of Formula (IV) isprotected with suitable protecting group R (as discussed above inrelation to Formula (IV) using variety of methods.

Various organic or inorganic bases may be employed, such astriethylamine, pyridine or potassium carbonate, with triethylamine beingpreferred.

For example, one method includes reacting 2,3-dichloro-6-nitro benzylalcohol—Formula (IV)—with alkyl or aryl sulphonyl halide in the presenceof a base, such as triethylamine or the like, preferably at atemperature of 35° C., or less, for a time preferably less than 8 hours.The sulphonyl halide is preferably added to the compound of Formula (IV)over an extended period of time at a temperature of 30° C., or less,with stirring. The reaction is not exothermic, which avoids impurityformation. The organic layer may then be separated, washed with an acidand neutralized with a base, then concentrated to obtain the compound ofFormula (V).

The alkyl sulphonyl halide is preferably C₁ to C₆, more preferably C₁ toC₄ straight or branched chain alkyl. The alkyl sulphonyl halide is mostpreferably methyl sulphonyl halide. In the aryl sulphonyl halide, thepreferred aryl groups are phenyl and p-toluyl.

Steps (i) and (ii) are preferably carried out without isolating thealcohol of Formula (IV).

(iii) According to yet another embodiment of the present invention thecompound of Formula (V) is alkylated with glycineethylester in anorganic solvent, such as acetonitrile, using base and a catalystpreferably, dimethyl amino pyridine. Suitable bases for this reactionare carbonates or alkali metal hydroxides, preferably anhydrouspotassium carbonate. Typically, the reaction is carried out at atemperature less than or equal to 60° C., more preferably less than orequal to 40° C. After completion of the reaction, the reaction mass isfiltered, and concentrated under vacuum to obtainethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine, which is further convertedto hydrochloride salt in suitable organic solvent such as ethyl acetateto obtain ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride, acompound of Formula (I).

In prior art processes, where the leaving group is bromo (e.g. U.S. Pat.No. 5,801,245, column 5, example 3, lines 6-25), the reaction withglycine ethyl ester hydrochloride requires 14 hrs reflux inTHF-triethylamine, which requires further purification by columnchromatography. Yield—87% w/w—Efficiency 60.20%.

In prior art processes, when the leaving group is chloro (e.g. US2003/0060630, page 5 [0040]), the reaction is carried out in highboiling solvent toluene, at 80° C. for 24 hrs using 10% w/wcetyltrimethylammonium bromide, which is an expensivecatalyst—Efficiency 66-71%.

In the process according to the invention, where the leaving group ismesyl or tosyl, for example, the reaction can be carried out at lowtemperature of 37-40° C. in acetonitrile as solvent, potassium carbonateas base and 0.2% w/w dimethyl amino pyridine as catalyst. Due to the lowreaction temperature, a relatively small level of impurities is formedgiving high yield and purity—Efficiency 75.52%.

In another aspect of the present invention, intermediateethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride of Formula(I), prepared by using process of the present invention, is converted toanagrelide by

(iv) Reducing nitro group of Formula (I) with suitable reducing agent toconvert it to amine of Formula (VI). Various methods may be employed tocarry out the nitro reduction, such as catalytic hydrogenation or metalreduction. Normally catalytic hydrogenation is carried out in thepresence of noble metal catalysts, such as palladium, platinum, or RaneyNickel on a carbon support. The source of hydrogen may be hydrogen gasor a hydrogen donating compound such as ammonium formate. Metalreduction may be carried out using tin, iron, or using stannous chloridewith an acid.

In the forgoing processes the preferred reduction is metal reductionusing stannous chloride and a preferred acid is hydrochloric acid. Thereaction is preferably carried out at a temperature of 50° C., or less.After completion of the reaction, the reaction mass is filtered,suspended in water and basified to obtain an amine of Formula (VI).

(v) Reacting the compound of Formula (VI) with cyanogen halide to formthe compound of Formula (VII) where the halide is as defined above,i.e., chloro, bromo or iodo. Normally the reaction is carried out usingcyanogen bromide in an aprotic inert organic solvent such as toluene,chlorobenzene, xylene, heptane and hexane. A preferred solvent istoluene. A preferred reaction temperature is from 80-150° C.

(vi) Cyclising compound of Formula (VII), to form a compound of Formula(II), i.e. anagrelide. The compound,ethyl-N-(5,6-dichloro-3,4-dihydro-2(1H) iminoquinazoline-3-acetatehydrobromide of Formula (VII), is readily converted to anagrelide ofFormula (II) with an organic base, such as triethylamine ordimethylaniline. The reaction may be carried out in an inert solvent.

The intermediate compound of Formula (V) represents a novel compound,per se, and this novel intermediate forms further aspects of the presentinvention.

In the present invention, the reaction is carried out by protecting thehydroxymethyl functionality of compound of Formula (IV). When usingmethane sulphonyl chloride in methylene chloride, the reaction was lessexothermic than in the prior art, and was more controllable with lessimpurity formation.

-   Overall yield:—76% (From compound III to compound I) with HPLC    purity of 98.5%

EXAMPLES

Further details of the invention are given in the examples below. Theexamples are provided for illustration only.

Example 1 Preparation of 2,3-dichloro-6-nitro benzyl methane sulphonate,a Compound of Formula (V)

Methylene chloride (2000 ml) and sodium borohydride (120 g) were chargedto a clean and dry flask and chilled to 0-5° C. Methanol (100 ml) wasadded slowly over a period of 20 minutes followed by2,3-dichloro-6-nitro benzaldehyde solution (500 g in 2000 ml ofmethylene chloride) over a period of 2 hours maintaining the temperatureat 0-5° C. and the contents were stirred at 0-5° C. for 1 hour. Aftercompletion of reaction, water (3000 ml) was added and stirred for 10minutes. The organic layer was separated, dried over sodium sulphate andwas filtered to get a clear filtrate.

To the clear filtrate triethylamine (460 ml), was slowly added over aperiod of 1 hour at 10-15° C., then methane sulphonyl chloride (325 ml)was added drop wise over a period of 2 hours maintaining temperature of10-15° C. and the reaction mass was allowed to attain room temperature.Further the reaction mass was stirred at room temperature for 5 hoursand after completion of reaction, the organic layer was washed withwater (1000 ml) twice, followed by 1N HCl solution (1000 ml) twice, 5%Sodium bicarbonate solution (1000 ml) twice, water (1000 ml) twice andwas dried over sodium sulfate. The clear organic layer was concentratedunder vacuum below 40° C. to give the title compound which was used inthe next step.

Example 2 Preparation of ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycinehydrochloride, a Compound of Formula (I)

2,3-dichloro-6-nitro benzyl methane sulphonate (Example 1) was dissolvedin acetonitrile (2400 ml). To this reaction mass were charged anhydrousPotassium carbonate (480 g), dimethyl amino pyridine (480 mg) andglycine ethyl ester (240 g) at room temperature. The contents werestirred at 37-40° C. for 24 hours. After completion of reaction, theinsolubles were filtered, washed with acetonitrile (120 ml). The clearfiltrate was concentrated and stripped off using ethyl acetate (240 ml).

Further ethyl acetate (1200 ml) was added, chilled the contents to 5-10°C., adjusted the pH to 2.0 using IPA-HCl at 5-10° C. The contents werestirred at 5-10° C. for 1 hour. The solids were filtered, washed withchilled ethyl acetate (120 ml) and dried under vacuum at roomtemperature for 4 hours to give the title compound (595 g, 76% yield,98.5% HPLC purity).

Example 3 Preparation of Anagrelide, a Compound of Formula (II) a)Preparation of Ethyl-5,6-dichloro-3,4-dihydro-2[1H]-iminoquinazolin-3-acetate hydrobromide

A solution of stannous chloride dihydrate (1850 gms) in concentrated HCl(6.7 liters) was added slowly to a cooled solution ofethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (595 gms) inconcentrated HCl (5.15 liters) maintaining temperature 15-20° C. over aperiod of 2 hours. The contents were heated slowly to 40-45° C. andstirred for 1 hour at 40-45° C. After completion of reaction, thecontents were cooled to 15-20° C., maintained for 15 minutes andfiltered.

The solids thus obtained were suspended in water (2.9 liters), adjustedthe pH of the reaction mass to 8.0-9.0 using potassium carbonatesolution (prepared by dissolving 376 gms of potassium carbonate in 4.25liters of water) at 0-5° C., extracted into toluene (3.0 liters×3),dried over sodium sulphate and clarified.

To the clear toluene layer, added Cyanogen bromide solution (prepared bydissolving 222 gms of cyanogen bromide in 655 ml of toluene) in 30minutes maintaining temperature 15-20° C. and stirred at 25-30° C. for 2hours. The contents were heated slowly to 105-110° C. maintained for 16hours at 105-110° C. After completion of reaction, the mass was cooledto 15-20° C. and stirred for 45 minutes. Filtered the material, washedwith chilled toluene (1.3 liters). The material was slurried in toluene(470 ml) at 15-20° C. for 1 hour, filtered, washed with cold toluene(160 ml) and dried under vacuum at 50-60° C. for 8 hours to give thetitle compound (445 gms).

b) Preparation of6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one [Anagrelide]

A mixture ofethyl-5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazolin-3-acetatehydrobromide (445 gms), isopropyl alcohol (4.45 liters) andtriethylamine (246 ml) was refluxed for 2 hours. After completion ofreaction, the mixture was cooled to 20-25° C., filtered, washed withchilled isopropyl alcohol (1.0 liters) and dried under vacuum at 50-55°C. for 6 hours to give the title compound (285 gms).

It will be appreciated that the invention described above may bemodified within the scope of the claims.

What is claimed is:
 1. A process for preparing anagrelide of Formula(II):

which comprises: (i) alkylating a compound of Formula (V):

where R is a leaving group other than hydrogen with glycine ethyl esterin a suitable solvent, using a base, to produce a compound of Formula(I′):

(ii) converting the compound of Formula (I′) to the hydrochloride saltin a suitable solvent, to obtain compound of Formula (I):

(iii) reducing the nitro group of Formula (I) with a suitable reducingagent to convert it to an amine of Formula (VI):

(iv) reacting the compound of Formula (VI) with a cyanogen halide toform compound of Formula (VII):

wherein halide is chloro, bromo or iodo; and (v) cyclising compound ofFormula (VII), to form compound of Formula (II).
 2. The processaccording to claim 1, wherein the group R is —SiR¹ ₃, where R¹ is asubstituted or unsubstituted alkyl.
 3. The process according to claim 1,wherein the group R is —CH₂Ar, where Ar stands for aryl.
 4. The processaccording to claim 1, wherein the group R is —COOR², where R² is alkylor aryl.
 5. The process according to claim 1, wherein the group R is—SO₂R³, where R³ is alkyl or aryl.
 6. The process according to claim 1,wherein a compound of Formula (IV):

is reacted to produce a compound of Formula (V):

where R is a leaving group other than hydrogen.
 7. The process accordingto claim 6, wherein the reaction is carried out in the presence of analkyl or aryl sulphonyl halide.
 8. The process according to claim 6,wherein the reaction is carried out in the presence of a base.
 9. Theprocess according to claim 6, wherein the reaction is carried out at atemperature of 35° C., or less.
 10. The process according to claim 6,wherein a compound of Formula (III)

is reduced to form the compound of Formula (IV):


11. The process according to claim 10, wherein the compound of Formula(IV) is not isolated.
 12. The process according to claim 1, wherein thereaction temperature of the alkylation step is 60° C., or lower.